Two-membrane medicated device for rate-controlled administration of prostaglandins

ABSTRACT

The present specification describes a medicated device adapted for a single, acute, and rate-controlled rectal or vaginal administration to a mammal of a lipophilic prostaglandin. The device accomplishes drug administration at an essentially time-independent rate of dosage. Further, the device advantageously results in the substantial exhaustion of the prostaglandin from the device at the conclusion of the single, acute use. The device comprises three elements: 
     (A) an inert resilient support means contoured for easy vaginal or rectal insertion; 
     (B) a first flexible polymer film layer affixed to the support means and containing the prostaglandin dispersed therethrough, this first polymer film not being rate limiting as to the release of drug from the device; and 
     (C) a second polymer film, laminated onto the first polymer film and providing a release rate therefrom of prostaglandin, which is rate limiting both as to the release of prostaglandin from the device and absorption rate by the rectal or vaginal tissues.

DESCRIPTION BACKGROUND OF THE INVENTION

The present invention relates to a device for a single, acute deliveryof a LAP (lipophilic anti-luteal/oxytocic prostaglandin) for theinduction of a discrete physiological event in a mammal. The inventionfurther relates to a controlled drug-delivery device, whereby the rateof dosage delivered is essentially time-independent.

The invention further relates to the method of use of the aforementioneddevice for uses in the reproductive cycle, e.g., obstetrical andgynecologic purposes. In particular, the invention relates to the use ofthe present device and the regulation of the mammalian estrous ormenstrual cycle, pregnancy interruption during the first or secondtrimester, the induction of labor at term, cervical dilatation, andevacuation of the uterine contents necessitated by fetal death in uteroor hydatidiform mole. Hence the invention relates to the acute use ofantifertility prostaglandins for the induction of discrete obstetric orgynecologic events. The present invention is therefore contrasted tochronic uses of pharmacologic agents for such purposes as suppressingovulation in otherwise menstruating females and the like.

PRIOR ART

Rectal or vaginal administration of therapeutic doses of numerouspharmacological agents is accomplished in a rate-controlled,time-independent manner employing numerous medicated devices. As willbecome apparent, however, none of these prior art devices will exhibitall of the various advantages and adaptations for use present in devicesin accordance with the present invention.

Such rate-controlled release devices are in contrast to other drugdelivery means such as suppositories formulated for either rectal orvaginal use. Suppositories release a therapeutic agent contained thereinas they melt down in the cavity into which they are placed. Hence therelease rate from suppositories is not rate-controlled, being subject tothe vagaries of the cavity into which they are inserted, much lesstime-independent. In this respect, suppositories are clearlydistinguished from the novel devices herein.

The prior art devices exhibiting rate-controlled release of atherapeutically active agent typically operate by encasing a drugreservoir with a drug-permeable, or otherwise drug-porous barrier. Seefor example U.S. Pat. No. 3,279,996, describing a drug encapsulated inpolymeric walls through which diffusion therethrough results in arate-controlled release. Other such rate-controlled membrane devicesinclude those specifically adapted for the prolonged release of drugfrom a drug-bearing reservoir, and include those of U.S. Pat. No.3,948,254, describing a reservoir of a solid drug carrier; U.S. Pat. No.3,926,188, describing a low water-soluble crystalline drug in apolymeric core lamina and interposed between release rate-controllinglaminae; U.S. Pat. No. 3,710,795, describing a polymeric matrix withdrug dispersed therethrough and being stressed by an elastic,rate-controlling membrane; U.S. Pat. No. 3,903,880, describing a drugmatrix reservoir enclosed in a vinylene-ethyl acetate copolymer barrier;U.S. Pat. No. 3,938,515, describing a drug with carrier enclosed with apolymeric membrane containing a permeability-modifying polymericadditive (e.g., a polyester); U.S. Pat. No. 3,911,911, describingcapsules with permeable walls of a silicone elastomer containingtherewithin progestational agents; and U.S. Pat. No. 3,854,480,describing a polymeric matrix containing drug particles dispersedtherethrough and surrounded by a drug-permeable membrane.

Numerous vaginal devices are known in the art, particularly for thesupply of either prostaglandins or progestational agents. These devicesinclude those described in U.S. Pat. No. 3,915,898, wherein a spongeimpregnated with a progestational compound is disclosed. In contrast tothe device of the present invention, the drug-bearing sponge does notprovide a controlled release therefrom.

Other examples of vaginal devices known in the art for the delivery ofdrug therefrom include medicated vaginal tampons, for example those ofU.S. Pat. No. 3,902,493 and British Pat. No. 1,480,615 (Derwent FarmdocCPI No. 79338V), where drug-bearing film coating of an ordinarycatamenial tampon is disclosed. Controlled release devices do, however,include those of U.S. Pat. No. 3,920,805, disclosingprostaglandin-containing silastic rings wherein the outer surface ofsaid ring has a prostaglandin dispersed therethrough, and U.S. Pat. No.4,043,339, describing disc-like silastic elastomers containingprostaglandins imbedded therewithin.

Other devices, specifically adapted for the prolonged release of drug,but not exhibiting a rate-controlled membrane, include devices describedin U.S. Pat. No. 3,921,636, describing a polymeric matrix through whichdrug is released from drug reservoirs contained therewithin, and U.S.Pat. No. 3,978,203, describing drug-containing biodegradable andmetabolizable polymeric matrices. Other devices containing polymeric anddrug matrices include those described in U.S. Pat. No. 3,975,350,wherein hydrophilic polyurethane systems are disclosed.

There are further known in the art ophthalmic devices providing atime-independent controlled rate of release of drug from such devicessuch as are described in U.S. Pat. No. 3,641,237. In particular, theseophthalmic devices comprise an inner drug-bearing film layerencapsulated by a water-swellable polymeric matrix in film form andlaminated to the drug bearing film for the delivery of water-solubleophthalmic drugs. Likewise there is described in U.S. Pat. No. 3,630,220ophthalmic devices comprising an inner drug reservoir, which israte-controlling as to the release of drug from the device, and an outerhydrophilic polymeric membrane, which provides compatability of thedevice with the ocular tissues.

SUMMARY OF THE INVENTION

The present invention provides a novel device for the delivery ofpharmacological agents. Particularly, the present invention providesdevices adapted for rectal or vaginal use. Further, the presentinvention specifically provides for medicated devices whereby lipophilictherapeutic agents are administered vaginally or rectally. Mostparticularly, the present invention relates to medicated devices for thevaginal or rectal administration of lipophilic anti-luteal/oxytocicprostaglandins.

The present invention further relates to medicated devices adapted for asingle and acute administration. Moreover, the invention particularlyprovides medicated devices wherein the release rate therefrom israte-controlled and essentially time-independent during the course oftherapeutic use therefrom.

The present invention most particularly relates to medicated devicescomprising three components: two membranes and a support means.Particularly, the present invention relates to medicated devicesexhibiting two flexible polymeric membranes, one serving as adrug-bearing membrane, the other a rate-controlling membrane.

Most particularly, the present invention provides:

a medicated device adapted for a single, acute, and rate-controlledvaginal or rectal administration to a female mammal of a therapeuticamount of a LAP (lipophilic anti-luteal/oxytocic prostaglandin)effective to accomplish a discrete event in the mammalian reproductivecycle;

said administration being of a predetermined TD (therapeutic duration);

said administration resulting in the release of LAP from said deviceduring the course of said administration at a predetermined, essentiallytime-independent RR (release rate); and

said administration resulting in the exhaustion of said LAP from saiddevice during the course of said treatment to the extent that themedicinal reuse of said device is essentially impossible; whichcomprises:

(1) a flexible polymeric DBM (drug-bearing membrane), containingdissolved and suspended therethrough said LAP and being furthercharacterized by:

(a) a D_(DBM) (diffusion coefficient of said DBM with respect to saidLAP) and an S_(DBM) (solubility in said DBM of said LAP);

(b) an SA (surface area) of said DBM sufficiently great such that the RF(release flux of said LAP released from said device), which RF is thequotient which is said RR divided by said SA, is substantially less thanthe absorption rate per unit area of said LAP by the rectal or vaginalepithelial tissues of said mammal in contact with said device duringsaid administration; and

(c) an essentially uniform T_(DBM) (thickness of said DBM) and aD_(DBM), (initial concentration of said LAP in said device), whichC_(DBM) is the quotient which is the amount of said LAP divided by thevolume of said DBM;

(2) a flexible, polymeric RCM (rate controlling membrane), beinglaminated onto a first surface of said DBM and being substantiallycoextensive therewith, being further characterized by:

(a) an S_(RCM) (solubility in said RCM of said LAP) and an essentiallyuniform T_(RCM) (thickness of said RCM); and

(b) D_(RCM) (diffusion coefficient of said RCM with respect to saidLAP), such that the R_(RCM) (resistance of said RCM), which R_(RCM) isthe quotient which is said T_(RCM) divided by the products of (i) K(partition coefficient between said DBM and RCM), which is the quotientwhich is said S_(DBM) divided by said S_(RCM), and (ii) said D_(RCM) isat least very much greater than the R_(DBM) (resistance of said DBM),which R_(DBM) is the quotient which is said T_(DBM) divided by saidD_(DBM) ; and

(3) a physiologically inert, resilient, and water-insoluble supportmeans, having the second surface of said DBM laminally affixed to atleast a portion of the surface thereof; being adapted, contoured, anddimensioned for accomodation of the entirety of said DBM on the surfacethereof and for easy and comfortable rectal or vaginal insertion andwithdrawal of said device; being essentially non-absorptive of said LAP;and being of substantially non-concave construction, whereby the surfaceof said device upon insertion is in essentially complete and intimatecontact with rectal or vaginal epithelial tissues and associatedsecretions;

said device being further characterized by

(a) said T_(RCM) being approximately

    (D.sub.RCM S.sub.RCM /RF)                                  Eq. 1

wherein RF, D_(RCM) and S_(RCM) are as defined above;

(b) a T₅₀, which is the time after TD for the RF to be reduced by 50percent, being approximately

    (ln 2) [P/(1-P)](TD)                                       Eq. 2

wherein P is the ratio of the amount of LAP remaining in said device atTD to the initial amount of LAP in said device, said P beingcharacterized by a preselected value less than about 0.42; and

wherein TD is as defined above;

(c) said T_(DBM) being approximately

    [P/(1-P)][(RF)(TD)/S.sub.DBM ]-T.sub.RCM /2K               Eq. 3

wherein K, TD, T_(RCM), RF, and P are as defined above; and

(d) said C_(DBM) being approximately

    ((RF)(TD)/(1-P)T.sub.DBM)                                  Eq. 4

wherein P, RF, TD, and T_(DBM) are as defined above.

As indicated above, devices in accordance with the present invention arespecifically adapted for the rectal or vaginal administration oflipophilic pharmacological agents, particularly lipophilicanti-luteal/oxytocic prostaglandins. For the purposes of the presentinvention, pharmacological agents are considered prostaglandins providedthey represent either a naturally-occurring prostaglandin or a chemicaland pharmacological analog thereof. For the purposes of the presentinvention, natural prostaglandins are those biosynthetic derivatives ofunsaturated fatty acids exhibiting anti-luteal or oxytocic properties.Thus the naturally-occurring prostaglandins include prostaglandin Acompounds, prostaglandin R compounds, prostaglandin C compounds,prostaglandin D compounds, prostaglandin F compounds, prostaglandin Fcompounds, thromboxanes, and prostacyclins. Prostaglandin analogstherefore include chemically modified substances which retain thecharacteristic antiluteal or oxytocic properties of the naturalprostaglandins. For the purposes of the present invention, prostaglandinanalogs are considered to retain the anti-luteal or oxytocic property ofthe corresponding natural prostaglandin provided that the potency ofthese analogs in the standard laboratory animal tests, hereinafterdescribed, is at least 0.1 times the potency of prostaglandin E₂ orprostaglandin F₂.

The therapeutic agent in accordance with the present invention isconsidered an anti-luteal/oxytocic prostaglandin provided that it iseither a natural prostaglandin or an analog thereof retaining at leastone-tenth the anti-luteal or oxytocic potency of either prostaglandin F₂or prostaglandin E₂. The anti-luteal potency of a natural prostaglandinor an analog thereof is assessed by its potency in standard laboratorytests designed to meausre luteolytic activity or the ability to causeregression of the corpus luteum. The standard experimental animal ofconvenience for assessing anti-luteal effects is the Golden hamster, ananimal in which prostaglandins, such as PGF₂, are known to terminateearly pregnancy by a direct lytic effect on the corpus luteum. While theuse of the Golden hamster as an experimental animal for assessing theanti-luteal effects of prostaglandins is widely known, see U.S. Pat. No.3,852,465 for a description of one such procedure.

The oxytocic potency of natural prostaglandins or analogs thereof isassessed in accordance with the present invention by the effect of theseagents on the pregnant mammalian myometrium. The standard laboratoryanimal of choice for assessing oxytocic potency is the Rhesus monkey(Macaca mulatta). Tests on the pregnant female Rhesus monkey designed tomeasure the amplitude and frequency of uterine contractions uponadministration of a naturally-occurring prostaglandin or analog thereofare widely known, e.g., Kirton, et al., New York Academy of Science180:455 (1971), Fuchs, et al., New York Academy of Science 180:531(1971), and Kirton, et al., Prostaglandins 1:319 (1972).

The lipophilicity of the anti-luteal/oxytocic prostaglandins inaccordance with the present invention is determined by standardtechniques. One especially simple and convenient technique in accordancewith the present invention for assessing lipophilicity is thedetermination of the n-octanol water partition coefficient. Thispartition coefficient is determined by placing the anti-luteal/oxytocicprostaglandin in an equilibrated mixture of n-octanol and water, shakingthe mixture until equilibrium and thereafter measuring the concentrationratio as between the n-octanol and water layers. The procedure isadvantageously carried out at ambient temperature (preferably about 25°C.) and the quantity of prostaglandins selected is less than thequantity soluble in the aqueous layer. The larger the ratio(concentration in n-octanol:concentration in water), the greater thelipophilicity. A natural prostaglandin or an analog thereof is deemedlipophilic provided its partition coefficient, i.e., ratio of theconcentration in n-octanol to the concentration in water, is about equalto or greater than that of prostaglandin F₂ in free acid form. Fornatural prostaglandins or analogs thereof which are carboxylic acids,lipophilicity may bne modified by derivitization of the carboxylic acidto its ester form. For example, prostaglandin F₂, methyl ester, issignificantly more lipophilic than prostaglandin F₂ in its free acidform. Thus for those anti-luteal/oxytocic prostaglandins which are lesslipophilic than PGF₂, esters thereof which are about equally lipophilicor more lipophilic than PGF₂ are contemplated for use in accordance withthe present invention.

In accordance, therefore, with the aforementioned criteria, naturalprostaglandins or analogs thereof which are both lipophilic andanti-luteal/oxytocic are considered to be LAP's or lipophilicanti-luteral/oxytocic prostaglandins in accordance with the presentinvention.

A LAP of the present invention is employed to accomplish a discreteevent in the mammalian reproductive cycle. While the treatment of humansis especially contemplated by medicated devices in accordance with thepresent invention, domestic animals and other mammalian species are alsocontemplated as subjects for use of devices of the present invention.The discrete events in the mammalian reproductive cycle induced by theemployment of devices of the present invention are those physiologicalevents which can be induced by LAP administration of about 72 hr. orless. Particularly, such discrete events are those which can be inducedby LAP administration with devices of the present invention in 24 hr. orless. Such discrete events in the mammalian reproductive cycle includeregression of a corpus luteum in estrous-cycling animals, abortion,labor induction, hydatidiform mole removal, uterine evacuation followingfetal death in utero, cervical dilatation (e.g., preliminary to adilatation and curretage), and treatment of purulent genital tractdiseases of domestic animals (e.g., pyometra). For each of these variousindications, the necessary dosage of a LAP and its required duration ofadministration upon vaginal or rectal administration can be readilyassessed. One particularly convenient means for assessing the necessarydosage and duration of treatment is by determination of the relativeamount of LAP required to stimulate the uterus of the pregnant Rhesusmonkey upon to stimulate the uterus of the pregnant Rhesus monkey uponvaginal administration.

Once a particular LAP has been selected and the discrete event in themammalian reproductive cycle for treatment is confronted, the desiredrelease rate (RR) from the device in accordance with the presentinvention and therapeutic duration of treatment (TD) are selected. Whilethe precise and optimal (i.e., acceptable therapeutic effect withminimization of side effects) release rate will vary depending upon theparticular mammal and the precise therapeutic duration of treatment andmay vary by up to about 50 percent from mammal to mammal, these valuesare nonetheless predetermined based upon experience and the knownpharmacological actions of the particular LAP. Especially important isthe known potency of the particular LAP on vaginal administration to theRhesus monkey, as indicated previously. Accordingly, the ordinarilyskilled physician or veterinarian will readily appreciate the factorsrelevant to determining both the release rate and therapeutic durationof treatment and select appropriate values for each employing ordinaryskill of those from this profession. For example, where relativelyshorter therapeutic durations of treatment are indicated (e.g.,indicated induction of labor for patients presenting toxemia ofpregnancy), somewhat higher release rates of a particular LAP(especially a LAP, such as prostaglandin E₂, which is hypotensive) willbe readily appreciated and selected.

As indicated previously, a medicated device in accordance with thepresent invention provides for a rate-controlled, essentiallytime-independent release rate during the therapeutic duration oftreatment. While a rate-controlled release makes reference to theabsence of an effect on release rate from the vagaries of the cavityinto which the medicated device is placed during its therapeutic use,the essentially time-independent release makes reference to theconstancy of the release rate from the initiation of treatment until theend of therapeutic duration of treatment. Accordingly, the release ratefrom the device, essentially a preset constant value, is hereinafterdesignated as "RR". Likewise, the predetermined therapeutic duration oftreatment is designated hereinafter as "TD". The product of these twopredetermined values (RR×TD) is the therapeutic amount of the LAPdelivered by the device for accomplishing the discrete event in themammalian reproductive cycle.

Devices constructed in accordance with the present invention contain twoflexible polymeric membranes; a drug-bearing membrane (DBM) and arate-controlling membrane (RCM). Such flexible polymeric membranes arecharacterized by certain readily ascertained physical properties withrespect to a LAP. In particular, the polymers are characterized by adiffusion coefficient with respect to a particular LAP and a solubilityfor a particular LAP in the polymer. Also in the construction of devicesin accordance with the present invention these flexible polymericmembranes will exhibit an essentially uniform thickness. Hence thepolymeric membranes will further exhibit resistances to the diffusion ofa particular LAP therethrough, which respective resistances are definedas the quotient obtained by dividing the thickness of the particular LAPby its diffusion coefficient.

Polymers are selected for use in devices of the present invention basedfirstly on their ability to solubilize the desired LAP and to permit thediffusion of the LAP therethrough. Accordingly, any of the polymericsubstances known in the art to be used in delivery devices forlipophilic drugs are readily employed by the present invention. Polymersare therefore broadly selected from numerous classes of compounds,including the polyurethanes, styrene-butadiene block copolymers,polyesters, polysiloxanes, polyvinyl chlorides, ethylene vinyl acetates,and polyalkylenes. As is apparent by reference to the above list ofsuitable polymers, the range of substances is limited only by theability of a particular polymer to solubilize and diffuse the LAP.

Secondly, the two polymers selected must preferably exhibitsubstantially different diffusion coefficients so that the relativeresistance in the DBM (R_(DBM)) is at least very much less than theresistance in the RCM (R_(RCM)). For this purpose a membrane resistanceis defined as the quotient of the thickness divided by the diffusioncoefficient for DBM and thickness divided by the product of thediffusion coefficient and the partition coefficient for R_(RCM).Therefore, for two polymers of significantly different resistances, thepolymer which will serve as the DBM is selected as the polymerexhibiting the lower diffusion coefficient, reserving the polymer withthe highest diffusion coefficient for the RCM. Diffusion coefficientsare preferred where R_(RCM) is at least 10 and more preferably at least100 times the R_(DBM).

As is apparent from the foregoing discussion regarding the relativeresistances of the DBM and RCM, the necessary constraints on resistancesare rigorously satisfied not only by reference to the relative diffusioncoefficients, but is further established by consideration of therelative membrane thickness. These relative membrane thicknesses aredetermined by certain mathematical expressions which provide approximatevalues therefor. With respect to the thickness of the rate-controllingmembrane, T_(RCM), its value is given approximately by Eq. 1, while thethickness of the drug-bearing membrane, T_(DBM), is given approximatelyby Eq. 3. With regard to Eq. 1 and 3 above, D_(RCM) is the diffusioncoefficient for the RCM while TD and RF are as defined above. Finally,K, the partition coefficient, represents the ratio which is the quotientof the solubility of LAP in the drug-bearing membrane (S_(DBM)) dividedby its solubility in the rate-controlling membrane (S_(RCM)). P is afraction determined by methods discussed below.

The solubilities and diffusion coefficients for polymers employed in theconstruction of devices in accordance with the present invention aredetermined by standard experimental means. For example, a two-celldiffusion chamber is readily employed in the determination of thediffusion coefficient and solubility of any polymer with respect to aparticular LAP. Briefly, the two-cell diffusion chamber consists of apolymeric membrane which separates the chamber's two cells. One cellcontains an inert medium with the LAP dissolved therethrough andmaintained at a constant concentration and the other cell contains onlythe inert medium itself. The concentration of drug in the second cell isthen plotted as a function of time, from the time at which the chamberis assembled. After an initial non-linear phase, the concentration ofLAP in the second cell is a linear function of time. For this linearfunction, the slope and abscissa (time-axis) intercept or time lag (TL)can be determined graphically, and represent respectively:

    slope=D.sub.RCM S.sub.RCM /T; TL=T.sup.2 /6D.sub.RCM,

wherein T represents the thickness of the RCM in the chamber. Thecorresponding DBM characteristics are determined identically.

Having thusly determined the diffusion coefficients and solubilities ofthe polymeric membranes, the predetermined, time-independent releaseflux of drug from the device during administration is thereafterdetermined. The release flux hereinafter "RF", is defined as the releaserate of drug from the device per unit area of the DBM. As indicatedabove, release rates for devices in accordance with the presentinvention are determined for each of the LAP's, based primarily on thepotency of the LAP and the desired therapeutic duration of treatment andare ordinarily between 1 μg/hr and 1 mg/hr.

One constraint in designing devices in accordance with the presentinvention is the provision of a surface area for the device,particularly the drug-bearing membrane thereof, which is sufficientlylarge as to permit a relatively small release flux from the device. Therelease flux from the device is the release rate of LAP from the deviceper unit surface area of the drug-bearing membrane of the device. Therelease flux from the device is the release rate of LAP from the deviceper unit surface area of the drug-bearing membrane of the device. Suchrelatively small release rates from the device assure that the animal orpatient in whom the device is placed will achieve a substantiallyuniform, time-independent absorption of the LAP. Accordingly, releasefluxes from the device are selected such that the release flux or RF issubstantially less than the absorption rate per unit area of the rectalor vaginal epithelial tissues of the mammal in whom the device is beingadministered. Within the range of release rates ordinarily employed withdevices in accordance with the present invention, devices exhibiting asurface area (SA) of the drug-bearing membrane thereof on the order of10-50 cm² are ordinarily sufficient.

A further characteristic of a device in accordance with the presentinvention is the exhaustion from such a device of an amount of the LAPsuch that the remaining quantity thereof is insufficient to permit amedicinal reuse of the device. For devices in accordance with thepresent invention, medicinal reuse is avoided provided that the ratio ofLAP in the device at the conclusion of the predetermined therapeuticduration to the amount of drug present in the device at the time of itsinsertion into the vagina or rectum is small. This ratio, hereinafterreferred to as "P", while necessarily ranging in value from some numbergreater than zero to some number less than 1, will be less than about0.42 for devices in accordance with the present invention.

By limiting P to a maximum value of about 0.42, an upper limit is placedon the ratio of the time following a first administration when therelease rate of the device during a second attempted administration willbe reduced to no more than one-half of the RF. When P is about 0.42,this ratio (T₅₀ /TD) will necessarily be less than 0.5. Thus anattempted reuser would obtain a release rate of less than one-half of RRfor any time greater than one-half of the predetermined therapeuticduration. When more severe constraints on non-reusability are required,devices in accordance with the present invention with lower values of Pare provided capable of meeting such more stringent requirement. Thus,for example, where the ratio T₅₀ /TD must be less than one-quarter,values of P less than about one-quarter are selected.

In contrast to the situation where very stringent requirements onreusability are mandated, selection of P values somewhat higher than0.42 are also provided in accordance with the present invention. Forexample, the value of P of about 0.6 may be preselected when the T₅₀ /TDratio can range as high as about 1. Obviously, however, in those caseswhere the 50 percent effective dose (ED₅₀) of a LAP is as much asone-half the 100 percent effective dose (ED₁₀₀) of that LAP, theselection of P values as high as 0.6 will be so high as to permit asundesired medicinal reuse of certain of the devices prepared inaccordance with the present invention.

In addition to providing a maximal value of T₅₀ /TD, the preselectedvalue for P likewise provides a minimum value for this ratio. Hence inorder to guarantee that a proper constraint on T₅₀ /TD will beaccomplished, a value of P so low that the desired T₅₀ /TD ratio fallsabove the minimum for that P value must be selected. For devices inaccordance with the present invention the minimum and maximum bounds ofthe T₅₀ /TD ratio are expressed by the following inequalities:

    T.sub.50 /TD<(1n2)P/(1-P)                                  Eq. 5

    T.sub.50 /TD>(1n2)P/(1-2P/3)                               Eq. 6

Within the range of values for T₅₀ /TD permitted by Eq. 5 and 6 above,devices constructed in accordance with the present invention furthercontain a T₅₀ /TD ratio determined by Eq. 6. For example when P is 0.25,T₅₀ /TD ratio will be between about 0.21 and 0.23.

The remaining design parameter for devices in accordance with thepresent invention, the thickness of the DBM, T_(DBM), and the initialconcentration of LAP are determined approxaimtely by Eq. 3 and 4,respectively.

Lastly, there is selected for use in accordance with the presentinvention a physiologically inert, resilient, and water-insolublesupport means. The selection of a suitable material for the supportmeans is as indicated above, made in part upon the physiologicalinertness of any prospective material. For example, materials known toirritate, react, or interact with rectal or vaginal epithelial tissuesare avoided. Further, material used for the support means must exhibit acertain resiliency, such that the physical integrity of the medicateddevice upon insertion is maintained. Resilient materials preferablyevidence some small degree of compressability or deformability such thatfacile administration is accomplished, but substantially rigid supportmeans (e.g., high density polyethylenes and nylons) may optionally beemployed. Finally, support means must be water insoluble, such thatduring the course of administration the secretions associated withvaginal or rectal epitherial tissue do not compromise the structuralintegrity of the device.

Just as the inner surface of the rate-controlling membrane is laminatedonto the outer surface of the drug-bearing membrane, the inner surfaceof the drug-bearing membrane is laminated onto the support means.Accordingly, the shape, dimensions, and contours of the device of thepresent invention are essentially those of the support means. Hence, thesupport means must be adapted, contoured and dimensioned practicably foraccomplishing the purposes of the instant invention. Specifically, thesupport means must facilitate the easy and comfortable insertion andwithdrawal of the device into or from the vagina or rectum.

The support means of the present invention also exhibits numerousmiscellaneous properties, namely being non-absorptive of the LAP andbeing constructed such that essentially the entire surface area would bein complete and intimate contact with vaginal or rectal epitherialtissues and associated secretions during administration. Accordingly,useful support means in accordance with the present invention are thosewhich are non-concave or at least substantially so.

In view of the foregoing, clearly one especially convenient and welladapted support means for devices in accordance with the presentinvention are catamenial tampons. Commercially available catamenialtampons ordinarily contain an acceptably-sized surface area, arenon-absorptive of lipophilic substances, and are water-insoluble.Moreover, catamenial tampons are specifically adapted, contoured anddimensioned for accomodation in the vagina.

Typically, catamenial tampons contain in addition to the corpus thereofa withdrawing means, ordinarily, simply a string. Devices in accordancewith the present invention likewise preferably include as a furtherelement thereof a withdrawing means, preferably a string or string-likeappendage non-removably attached to the device itself.

There is accordingly provided medicated devices in accordance with thepresent invention which are surprisingly and unexpectedly capable oftime-independent release of drug during a predetermined therapeuticduration, while avoiding the possibility of reuse of such devicesthereafter. Moreover, extended uses of devices in accordance with thepresent invention beyond their intended therapeutic duration, results ina surprisingly and unexpectedly rapid reduction in release ratetherefrom, whereby physiologically consequential dosages from suchextended administrations are minimized, if not avoided. Thus, thecoupling in devices in accordance with the present invention of atime-independent release rate with non-reusability provides asurprisingly and unexpectedly improved means for the induction ofdiscrete events in mammalian reproductive cycle. Hence, such devicesavoid the difficulties inherent in prior art time-independent releasedevices where reusability creates serious disposal problems and drugmisuse problems.

BRIEF DESCRIPTION OF THE DRAWING

The drawing provides three views of a medicated device in accordancewith the present invention, which drawing is not drawn to scale, butrather drawn to more clearly reflect the construction and operation ofdevices in accordance with the invention.

FIG. 1 depicts the device, further providing a cut-away view of theinterior thereof, and depicts an embodiment exhibiting the optionalwithdrawing means.

FIG. 2 provides a transverse cross-section of the device of FIG. 1.

FIG. 3 provides a longitudinal cross-section of the device of FIG. 1.

DETAILED DESCRIPTION OF THE DRAWING

The medicated device of the present invention has an outer surface (11)for its rate-controlling membrane or RCM (12). This rate-controllingmembrane (RCM) is laminated onto the drug bearing membrane or DBM (13)and is substantially co-extensive therewith. The inner surface of thisdrug-bearing membrane (DBM) is then laminally affixed onto the supportmeans (14), constituting a device in accordance with the presentinvention.

Finally the withdrawing means (15) is optionally attached to a device inaccordance with the present invention, particularly being attached (asindicated in the drawing) non-removably to the support means.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 Methodology formedicated device fabrication.

A. Polyurethanes are analyzed in a two cell diffusion chamber until twopolyurethanes of substantially differing (i.e., 10-100 fold) diffusioncoefficients are obtained. The polymer of higher diffusion coefficientis employed in the drug-bearing membrane or DBM while the polymer withthe lower diffusion coefficient is reserved for the rate-controllingmembrane or RCM.

B. A commercially available, compressed cotton catamenial tampon isselected as a support means. Membranes are prepared for lamination ontothe tampon by a dip-coating method, employing an inverted test tube formembrane casting. Accordingly, a test tube is selected whose diameter isequal to or slightly less than the diameter that the catamenial tampone.g., 5 ml. Firstly, the drug-bearing membrane is casted onto the testtube by dipping into a polymer-LAP containing solution. A water-miscibleorganic solvent, e.g., tetrahydrofuran is selected and polymer (3-20% byweight) and LAP (0.5-10% by weight) are added thereto. Thereafter, atest tube (e.g., 5 ml.) is inserted and slowly withdrawn from thesolution. The withdrawal rate is adjusted to obtain the desiredthickness (T_(DBM)). After drying and trimming, a second dip-coating isundertaken, employing a solution of the RCM polymer.

C. The laminated polymeric membranes prepared in part B are removed fromthe test tube by soaking in water (1-2 min.) and thereafter affixed tothe catamenial tampon selected in part B. Securing of the laminatedmembranes onto the tampon may be accomplished by string tying at thebase of the catamenial tampon (i.e., the juncture of the stringwithdrawing means to the tampon corpus).

In constructing devices in accordance with Example 1, the C_(DBM),T_(RCM), and T_(DBM) are determined approximately from equationsdescribed above. These equations employ experimentally determined valuesfor solubilities and diffusion coefficients and preselected values forP, RF, and therapeutic duration. In order to obtain the desired C_(DBM),adjustments are made in the concentration of LAP in the solutionemployed in dip-coating the DBM. Likewise, LAP in the solution employedin dip-coating the DBM. Likewise, as indicated above, withdrawal ratesof the test tube for coating both the DBM and RCM are adjusted so as toobtain the desired T_(RCM) and T_(DBM).

Adjustments in procedures to obtain desired values for C_(DBM), T_(TCM),T_(DBM) are obtained by experimental casting, such procedures are wellwithin the ordinary skill of the art.

Moreover, the approximate values for C_(DBM), T_(RCM), T_(DBM) as givenin the equation are employed in the construction of devices of thepresent invention. When such constructed devices exhibit the desiredcharacteristics (e.g., for RF and TD), then values for C_(DBM), T_(RCM)and T_(DBM) are precisely those indicated by the aforementionedequations. However, where performance characteristics are obtained fromsuch constructed devices, values for C_(DBM), T_(RCM), and T_(DBM) areadjusted by amounts not in excess of 10 percent until devices of desiredperformance are obtained. Such modifications in C_(DBM), T_(RCM),T_(DBM) are accomplished in accordance with methods obvious to those ofordinary skill in the art. For example, devices in accordance with thepresent invention wherein the RF is inadequate will require reduction ofthe T_(RCM) so that the desired, higher RF is exhibited. In such a casethe approximate value for the T_(RCM) given by the above equationtherefore is adjusted upward by not more than about 10 percent, thusyielding the device with the desired RF.

We claim:
 1. A medicated device adapted for single, acute, andrate-controlled vaginal or rectal administration to a female mammal of atherapeutic amount of LAP (lipophilic anti-luteal/oxytocicprostaglandin) effective to accomplish a discrete event in the mammalianreproductive cycle selected from the group consisting of(a) estrousinduction, (b) menses induction, (c) cervical dilatation, (d) abortion,(e) labor induction, and (f) uterine evacuation subsequent to fetaldeath in utero or hydatidiform mole; said administration being of apredetermined TD (therapeutic duration) of less than about 72 hours;said administration resulting in the release of LAP from said deviceduring the course of said administration at a predetermined, essentiallytime-independent RR (release rate) between about 1 μg and 1 mg per hour;and said administration resulting in the exhaustion of said LAP fromsaid device during the course of said treatment to the extent that themedicinal reuse of said device is essentially impossible; whichcomprises: (1) a flexible polymeric DBM (drug-bearing membrane),containing dissolved and suspended therethrough said LAP and beingfurther characterized by:(a) a D_(DBM) (diffusion coefficient of saidDBM with respect to said LAP) and an S_(DBM) (solubility in said DBM ofsaid LAP); (b) an SA (surface area) of said DBM on the order of 10-50cm², being sufficiently great such that the RF (release flux of said LAPreleased from said device), which RF is the quotient which is said RRdivided by said SA, is substantially less than the absorption rate perunit area of said LAP by the rectal or vaginal epithelial tissues ofsaid mammal in contact with said device during said administration; and(c) an essentially uniform T_(DBM) (thickness of said DBM) and a D_(DBM)(initial concentration of said LAP in said device), which C_(DBM) is thequotient which is the amount of said LAP divided by the volume of saidDBM; (2) a flexible, polymeric RCM (rate controlling membrane), beinglaminated onto a first surface of said DBM and being substantiallycoextensive therewith, being further characterized by:(a) an S_(RCM)(solubility in said RCM of said LAP) and an essentially uniform T_(RCM)(thickness of said RCM); and (b) D_(RCM) (diffusion coefficient of sadRCM with respect to said LAP), such that the R_(RCM) (resistance of saidRCM), which R_(RCM) is the quotient which is said T_(RCM) divided by theproducts of (i) K (partition coefficient between said DBM and RCM),which is the quotient which is said S_(DBM) divided by said S_(RCM) and(ii) said D_(RCM), is at least very much greater than the R_(DBM)(resistance of said DBM), which R_(DBM) is the quotient which is saidT_(DBM) divided by said D_(DBM) ; and (3) a physiologically inert,resilient, and water-insoluble support means, having the second surfaceof said DBM laminally affixed to at least a portion of the surfacethereof; being adapted, contoured, and dimensioned for accomodation ofthe entirety of said DBM on the surface thereof and for easy andcomfortable rectal or vaginal insertion and withdrawal of said device;being essentially non-absorptive of said LAP; and being of substantiallynon-concave construction, whereby the surface of said device uponinsertion is in essentially complete and intimate contact with rectal orvaginal epithelial tissues and associated secretions; said device beingfurther characterized by(a) said T_(RCM) being approximately

    D.sub.RCM S.sub.RCM /RF                                    Eq. 1

wherein RF, D_(RCM) and S_(RCM) are as defined above; (b) said T₅₀,which is the time after TD for the RF to be reduced by 50 percent, beingapproximately

    (1n 2)[P/(1-P](TD)                                         Eq. 2

wherein P is the ratio of the amount of LAP remaining in said device atTD to the initial amount of LAP in said device, said P beingcharacterized by a preselected value less than about 0.42; and whereinTD is as defined above;(c) said [C_(DBM) ]T_(DBM) being approximately

    [P/(1-P)][(RF)(TD)/S.sub.DBM ]-T.sub.RCM 2K                Eq. 3

wherein K, TD, T_(RCM), RF, and P are defined as above; and (d) saidC_(DBM) being approximately

    ((RF)(TD)/(1-P)T.sub.DBM)                                  Eq. 4

wherein P, RF, TD, and T_(DBM) are as defined above.
 2. A medicateddevice in accordance with claim 1, wherein said LAP is 15-methyl-PGF₂,methyl ester.